The overall objective of this competitive renewal proposal is to positionally clone the type 2 diabetes mellitus (T2DM) susceptibility gene on chromosome 1q21-q24 using state-of-the-art molecular and statistical genetic approaches in a unique founder population, the Old Order Amish. Our study represents a part of a larger collaborative venture involving several other groups who have also demonstrated linkage to T2DM in this region, and indeed a major component of our study will take advantage of a dense set of 2,200 single nucleotide polymorphism (SNP) markers to be genotyped across this region in six populations through a separately funded mechanism. In the prior grant period, through genome-wide analysis in the Amish, we identified several regions that are likely to harbor T2DM susceptibility genes, including a region on chromosome 1q21-q24 (LOD = 2.38; p = 0.0008). Initial fine mapping using over 600 SNP markers spaced throughout this region provide further evidence for an important T2DM gene in this region. To clone this gene, we will exploit the extended linkage disequilibrium (LD) in the Amish, a relatively young founder population by systematically performing LD mapping with densely distributed SNPs within the linked region. We will then replicate our findings and further localize the gene by genotyping the same SNPs in other populations with evidence for linkage to this region including Pima Indians, Utah, U.K. and French Caucasians, and Chinese, as well as large case control populations of U.S. Caucasians and African Americans from the Atherosclerosis Risk in Communities (ARIC) and NHANES III studies. We expect that LD mapping across populations will localize the putative gene to approximately 1 Mb or less, at which point, exhaustive positional candidate gene analysis will be performed to identify the gene and its pathogenic variant/haplotype. Strengths of this application include (1) access to large numbers of Amish samples from well characterized pedigrees, (2) substantial progress in localizing the chromosome 1q21-q24 T2DM susceptibility gene during the prior grant period, (3) a highly productive interdisciplinary research team at the University of Maryland, (4) state of- the-art high throughput genotyping and DNA sequencing facilities, and (5) ongoing collaboration and unprecedented collegiality of other groups working on chromosome 1q21-q24. Discovery of T2DM susceptibility genes will provide critical insights into molecular mechanisms that will impact substantially on the care and quality of life of millions of Americans with T2DM.